Compositions and methods for stimulating hair growth

ABSTRACT

Methods and compositions for stimulating the growth of hair are disclosed wherein said compositions include a cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by the formula I 
     
       
         
         
             
             
         
       
         
         
           
             wherein the dashed bonds represent the presence or absence of a double bond which can be in the cis or trans configuration and A, B, Z, X, R 1  and R 2  are as defined in the specification and a penetration enhancer. Such compositions are used in stimulating hair growth of human or non-human animals.

RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/829,273, filed Aug. 18, 2015, which is a continuation of U.S. patentapplication Ser. No. 14/163,954, filed Jan. 24, 2014, now U.S. Pat. No.9,138,480, issued Sep. 22, 2015, which is a continuation of U.S. patentapplication Ser. No. 12/940,711, filed Nov. 5, 2010, now abandoned,which claims the benefit of U.S. Provisional Patent Application No.61/259,368, filed Nov. 9, 2009, each of which are hereby incorporated byreference in their entireties.

FIELD OF THE INVENTION

Disclosed herein are compositions and methods for stimulating the growthof hair and treating disorders resulting in hair loss wherein saidcompositions include a cyclopentane heptanoic acid, 2-cycloalkyl orarylalkyl compound represented by the formula I:

wherein the dashed bonds represent the presence or absence of a doublebond which can be in the cis or trans configuration and A, B, Z, X, R₁and R₂ are as defined in the specification and a penetration enhancer.Such compositions are used in stimulating hair growth of human ornon-human animals.

BACKGROUND OF THE INVENTION

Dermatologists recognize many different types of hair loss, the mostcommon being “alopecia” or “baldness” wherein humans (mostly males)begin losing scalp hair at the temples and on the crown of their head.However, hair loss may be due to many other disorders.

Hair loss is often accompanied by a change in the hair growth cycle. Allmammalian hair passes through a life cycle that includes the anagenphase, the catagen phase and the telogen phase. The anagen phase is theperiod of active hair growth. In the scalp, this phase lasts from 3-5years. The catagen phase is a short 1-2 week transitional phase betweenthe anagen phase and the telogen phase. The final telogen phase isconsidered a “resting phase” where all growth ceases. This phase is alsorelatively short-lived lasting about 3-4 months before the hair is shedand a new one begins to grow. With the onset of baldness, a successivelygreater proportion of hairs are in the telogen phase withcorrespondingly fewer in the active growth anagen phase.

Additionally, different types of hair exist including terminal hairs,vellus hairs and modified terminal hairs. Terminal hairs are coarse,pigmented, long hairs in which the bulb of the hair follicle is seateddeep in the dermis. Vellus hairs, on the other hand, are fine, thin,non-pigmented short hairs in which the hair bulb is locatedsuperficially in the dermis. Modified terminal hairs are seen in eyelashes and eye brows. As alopecia progresses, a transition takes placewherein the hairs themselves change from the terminal to the vellustype. Accordingly, alopecia (baldness) also includes a deficiency interminal hairs.

One non-drug treatment for alopecia is hair transplantation. Plugs ofskin containing hair are transplanted from areas of the scalp where hairis growing to bald areas. This approach can be reasonably successful;however it is costly, time-consuming and painful. Other non-drug relatedapproaches to treating alopecia include ultra-violet radiation, massage,psychiatric treatment and exercise therapy. None of these approaches,however, have been generally accepted as effective. Even such things asrevascularization surgery or acupuncture have shown little, if any,effect.

SUMMARY OF THE INVENTION

Compositions and methods are disclosed herein for topical application ofan effective amount of at least one penetration enhancer andcyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compoundrepresented by the formula I:

wherein the dashed bonds represent the presence or absence of a doublebond which can be in the cis or trans configuration, A is an alkylene oralkenylene radical having from two to six carbon atoms, which radicalcan be interrupted by one or more oxo radicals and substituted with oneor more hydroxy, oxo, alkyloxy or alkylcarboxy groups wherein the alkylradical comprises from one to six carbon atoms; B is a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from the group consisting of hydrogen, a lower alkyl radicalhaving from four to ten carbon atoms wherein the heteroatom is selectedfrom the group consisting of nitrogen, oxygen and sulfur atoms; X is—N(R₄)₂ wherein R₄ is selected from the group consisting of hydrogen, alower alkyl radical having from one to six carbon atoms,

wherein R₅ is a lower alkyl radical having from one to six carbon atoms;Z is ═O; one of R₁ and R₂ is ═O, —OH or a —O(CO)R₆ group, and the otherone is —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or

—(CH₂)mR₇ wherein m is 0 or an integer of from 1 to 10, and R₇ iscycloalkyl radical, having from three to seven carbon atoms, or ahydrocarbyl aryl or heteroaryl radical, as defined above in free form ora pharmaceutically acceptable salt thereof, in association with apenetration enhancer in particular formulations adapted for topicalapplication to mammalian skin.

In one embodiment, the cyclopentane heptanoic acid, 2-cycloalkyl orarylalkyl compound represented by the formula I is the compoundbimatoprost.

Another embodiment includes a composition comprising bimatoprost at aconcentration of about 0.001-1.5% w/w, from 0.01-1.0% w/w, from0.02-1.0% w/w, 0.03 to about 1.0% w/w, 0.03 to 0.9% w/w, 0.04 to 0.8%w/w, 0.05-0.7% w/w, 0.06%-0.6% w/w, 0.07%-0.5% w/w, 0.08-0.4% w/w,0.09-0.3% w/w, 0.1% w/w, 0.2% w/w, 0.3% w/w, 0.4% w/w, 0.5% w/w, 0.6%w/w, 0.7% w/w, 0.8% w/w, 0.9% w/w and 1.0% w/w. The following excipientsmaybe also be included: Carbomer at a concentration of about 0.05-1.0%w/w; base at a concentration of about 0.01 to about 2.0% w/w; ethanol ata concentration of about 10 to about 90% w/w; glycerin at aconcentration of about 1.0 to about 20% w/w; diethylene glycol monoethylether at a concentration of about 1.0 to about 50% w/w; polysorbate 20at a concentration of about 0.1 to about 5.0% w/w; polysorbate 40 at aconcentration of about 0.1 to about 5.0% w/w; polysorbate 60 at aconcentration of about 0.1 to about 5.0% w/w; polysorbate 80 at aconcentration of about 0.1 to about 5.0% w/w; PPG-5 ceteth-20 at aconcentration of about 0.1 to about 5.0% w/w; oleic acid at aconcentration of about 0.1 to about 5.0% w/w; isostearyl isostearate ata concentration of about 0.1 to about 10% w/w; isopropyl myristate at aconcentration of about 0.1 to about 10% w/w; dipropylene glycol dimethylether at a concentration of about 1 to about 50% w/w; diethylene glycolat a concentration of about 1 to about 50% w/w; dipropylene glycol at aconcentration of about 1 to about 50% w/w; caprylic/capric at aconcentration of about 0.1 to about 10% w/w; benzyl alcohol at aconcentration of about 0.1 to about 2.0% w/w; silicone at aconcentration of about 0.1 to about 10% w/w; and/or water at aconcentration of about 0 to about 90% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.10% w/w; NaOH at about 0.035% w/w;ethanol at about 15.0% w/w; diethylene glycol monoethyl ether at about10.0% w/w; and water at about 74.8% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.15% w/w; triethylamine (TEA) atabout 0.22% w/w; ethanol at about 15.0% w/w; diethylene glycol monoethylether at about 10.0% w/w; polysorbate 20 at about 4.0% w/w; and water atabout 70.5% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.125% w/w; TEA at about 0.18% w/w;ethanol at about 30.0% w/w; diethylene glycol monoethyl ether at about20.0% w/w; and water at about 49.59% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.10% w/w; TEA at about 0.15% w/w;ethanol at about 30.0% w/w; propylene glycol at about 20% w/w; and waterat about 49.7% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.20% w/w; TEA at about 0.22% w/w;ethanol at about 60.0% w/w; glycerin at about 5.0% w/w; and water atabout 34.48% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w;ethanol at about 60.0% w/w; polysorbate 20 at about 4.0% w/w; and waterat about 35.27% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w;ethanol at about 50.0% w/w; diethylene glycol monoethyl ether at about10% w/w; polysorbate 20 at about 4.0% w/w; and water at about 35.27%w/w.

The compositions were manufactured using the following generalprocedure. Non-aqueous components (e.g. bimatoprost, ethanol, glycols)were combined in a beaker and stirred using a propeller type overheadmixer until the solution was clear. Water was added to the non-aqueousmixture followed by the addition of the thickening agent. Upondispersion of the thickening agent, a base was added to neutralize thepolymer and thicken the solution into a gel.

DETAILED DESCRIPTION

Bimatoprost is a moderately soluble compound intended for topicaldelivery to the skin to stimulate hair growth. Hair growth includes,without limitation, stimulating the conversion of vellus hair to growthas terminal hair as well as increasing the rate of growth of terminalhair. Embodiments disclosed herein provide formulations of bimatoprostand similar compounds with penetration enhancers. These penetrationenhancers facilitate active component penetration and/or maintenance attheir site of action in the skin. Formulations disclosed herein can beself-preserved or contain an antimicrobial agent such as benzyl alcohol.

In accordance with embodiments disclosed herein, active components arerepresented by

The active components are provided in particular formulations thatinclude penetration enhancers. Some examples of representative compoundsuseful in the practice of embodiments disclosed herein include thecompounds shown in Table 1:

TABLE 1 Representative Compounds cyclopentaneheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneN,N-dimethylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-penten-yl)-3,5-dihydroxy,[1_(α),2_(β),3_(α),5_(α)] cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-pent-enyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-trifluoromethylphenoxy-1-trans-pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneN-isopropyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihy droxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentane N-ethylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentane N-methylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneheptenamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-butenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)]

In one embodiment, the compound is a cyclopentane heptanoic acid,2-(phenyl alkyl or phenyloxyalkyl) represented by the formula II:

wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y isselected from the group consisting of alkyl, halo, e.g. fluoro, chloro,etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy, halosubstituted alkyl wherein said alkyl radical comprises from one to sixcarbon atoms, etc. and n is 0 or an integer of from 1 to 3 and R₃ is ═O,—OH or —O(CO)R₆ wherein R₆ is as defined above or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the compound is a compound of formula III:

wherein hatched lines indicate α configuration, solid triangles are usedto indicate β configuration. In another embodiment, y is 1 and x is 0and R₁, R₂ and R₃ are hydroxy.

One exemplary compound is cyclopentane N-ethylheptanamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy,[1_(α),2_(ß),3 _(α),5_(α)], also known as bimatoprost and sold under thename of LUMIGAN® by Allergan, Inc., California, USA. This compound hasthe following structure:

The synthesis of the above compounds has been disclosed in U.S. Pat. No.5,607,978 which is incorporated by reference in its entirety.

Effective amounts of the active compounds can be determined by one ofordinary skill in the art but will vary depending on the compoundemployed, frequency of application and desired result. The compound willgenerally range from about 1×1⁻⁷ to about 50% w/w of the composition, inone embodiment from about 0.001 to about 50% w/w of the composition andin another embodiment from about 0.1 to about 30% w/w of thecomposition. Ranges of within about 10-50% w/w; about 20-50% w/w; about30-40% w/w and about 35% are also included.

The pharmaceutical formulations disclosed herein can include one or morepenetration enhancers. The phrase “penetration enhancers” includes anyagent that facilitates the transfer of active components to their siteof action or maintains them at their site of action. Non-limitingexamples of classes of appropriate penetration enhancers includealcohols, glycols, fatty acids, ethers, esters, occlusive agents andsurface active agents. Representative examples of these classes areprovided below.

Alcohols include, without limitation, ethanol, propanol, N-propanol,isopropanol, butyl alcohol, octanol, benzyl alcohol and acetyl alcohol,in one embodiment, as described in U.S. Pat. No. 5,789,244, the entirecontents of which are incorporated by reference herein. Fatty alcoholsinclude, for example, stearyl alcohol and oleyl alcohol.

Glycols include, without limitation, glycerine, propyleneglycol,polyethyleneglycol and other low molecular weight glycols such asglycerol and thioglycerol.

Fatty acids, esters and ethers include, without limitation, oleic acid,palmitoleic acid, straight chain C₄-C₂₀ saturated monocarboxylic anddicarboxylic acids, octanoic and decanoic acids, methyl laurate, ethyloleate, polyethylene glycol monolaurate, propylene glycol monolaurate,propylene glycerol dilaurate, glycerol monolaurate, glycerol monooleate,isopropyl n-decanoate, octyldodecyl myristate, diethylene glycolmonoethyl ether, diethylene glycol monomethyl ether and compoundswherein a C₂-C₄ alkane diol or triol is substituted with one or twofatty ether substituents.

Occlusive agents include, without limitation, silicones, mineral oilsand greases, long chain acids, animal fats and greases, vegetable fatsand greases, water insoluble polymers, paraffin, paraffin oil, liquidparaffin, petrolatum, liquid petrolatum, white petrolatum, yellowpetrolatum, microcrystalline wax and ceresin.

Surface active agents include without limitation, polysorbate 20, 40, 60and 80, TWEEN® (20, 40, 60, 80), POLOXAMER® (231, 182, 184), sodiumdodecyl sulfate (SDS), lecithin, lysolecithin,nonylphenoxypolyoxyethylene, lysophosphatidylcholine, polyethylenglycol400, polyoxyethylene ethers, polyglycol ether surfactants, DMSO, sodiumlaurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, andbenzalkonium chloride.

Additional penetration enhancers will be known to those of ordinaryskill in the art of topical drug delivery, and/or are described in thepertinent texts and literature.

Embodiments disclosed herein can also include viscosity increasingagents. Appropriate agents include, without limitation, methylcellulose,polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid andchondroitin sulfate.

Certain embodiments disclosed herein can include preservativesincluding, without limitation, benzyl alcohol, benzalkonium chloride,chlorhexidine, chlorobutanol, methyl-, propyl-, orbutyl-parahydroxybenzoic acids, phenylmercuric salts including, withoutlimitation, nitrate, chloride, acetate, and borate and betain.

Various other additives may be included in the compositions of thepresent invention in addition to those identified above. These include,but are not limited to, antioxidants, astringents, perfumes, emollients,pigments, dyes, humectants, propellants, and sunscreen agents, as wellas other classes of materials whose presence may be cosmetically,medicinally or otherwise desirable. The compositions and formulationsmay also be taken in conjunction with minoxidil and propecia.

Compositions can also be formulated as “slow-releasing” formulations sothat the activity of active components is sustained for a longer periodof time between treatments.

While particular embodiments disclosed herein can include each of thecomponents discussed above, other particular embodiments can be requiredto be “substantially free” of one or more of these components in variouscombinations. “Substantially free”, as used herein, means that thecomponent is not added to a formulation and cannot be present in anyamount greater than about 1% w/w.

While not limiting the scope of express exclusion of the precedingparagraph, particular embodiments disclosed herein can be substantiallyfree of one or more of bimatoprost, carbomer, NaOH (s), TEA, ethanol,glycerin, diethylene glycol, monoethyl ether, propylene glycol,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, PPG-5ceteth-20, oleic acid, isostearyl isostearate, isopropyl myristate,dipropylene glycol dimethyl ether, diethylene glycol, dipropyleneglycol, triglycerides, caprylic/capric, benzyl alcohol, silicone andwater.

All components of formulations described herein will be included inamounts that are dermatologically-acceptable. As used herein,“dermatologically-acceptable” means that the compositions or componentsthereof are suitable for use in contact with human skin without unduetoxicity, incompatibility, instability, allergic response, and the like.As used in herein as applied to active agents and excipients, the term“about” refers to variations in concentrations which are considered tobe bioequivalent.

Embodiments disclosed herein find application in mammalian species,including both humans and animals. In humans, the compounds ofembodiments disclosed herein can be applied without limitation, to thescalp, face, beard, head, pubic area, upper lip, eyebrows, and eyelids.The compositions of the present inventions may be used for treatingvarious hair loss disorders including but not limited to alopeciaareata, telogen effluvium, anagen effluvium, cicatricial alopecia andscarring alopecia; hair shaft abnormalities such as trichorrexis nodosa,loose anagen syndrome, trichotillomania and traction alopecia;infectious hair disorders such as tiniea capitis, sebohorreicdermatitis, and follicullitus of the scalp; genetic disorders such asandrogenetic alopecia and patients undergoing hair loss due tochemotherapy, hormonal imbalance (e.g., thyroid conditions such ashypothyroidism and hyperthyroidism, pregnancy, child birth,discontinuation of birth control pills and changes in menstrual cycle),fungal infection of the scalp such as ringworm, medicines which causehair loss such as anti-coagulants, medicine for gout, depression, highblood pressure and certain heart medications. The formulations of thepresent invention may be used to treat hair loss related to otherdisease such as diabetes, lupus, and poor nutrition, mental and physicalstress such as due to surgery, illness and high fever. Environmentalfactors and chemicals used in hair treatment (dying, tinting andbleaching).

In animals raised for their pelts, e.g., mink, the formulations can beapplied over the entire surface of the body to improve the overall peltfor commercial reasons. The process can also be used for cosmeticreasons in animals, e.g., applied to the skin of dogs and cats havingbald patches due to mange or other diseases causing a degree ofalopecia.

The compositions and methods of the present invention may be applied topatients suffering from hair loss or in healthy patients simply wantingto increase hair growth in any part of the body.

The compositions disclosed herein are formulated for topicaladministration. The term “topical administration” as used hereinincludes applying a formulation as described herein to the outer skin orhair. The application will generally occur at or near the area ofdesired hair growth.

Accordingly, appropriate formulation or composition types include,without limitation, solutions, gels, ointments, foams, films, liniments,creams, shampoos, lotions, pastes, jellies, sprays and aerosols. Suchformulation types can be applied in swaths, patches, applicators orthrough the use of impregnated dressings depending on the situation andpart of the body to be treated.

Typically, the formulations described herein will be applied repeatedlyfor a sustained period of time to the part of the body to be treated. Inparticular embodiments, formulations disclosed herein can include one ormore applications daily, one or more applications weekly, one or moreapplications monthly or one or more applications yearly for a period oftreatment of at least one day, at least one week, at least one month, atleast one year or until the treatment has achieved or achieved andmaintained a desired result.

Formulations described herein will be administered in safe and effectiveamounts. As used herein, “safe and effective amounts” include an amountsufficient so that the composition provides the desired hair growthstimulation effect at a reasonable benefit/risk ratio attendant with anymedical treatment. Within the scope of sound medical judgment, theamount of active components used can vary with the particular conditionbeing treated, the severity of the condition, the cause of thecondition, the duration of the treatment, the specific active componentemployed, its concentration, the specific vehicle utilized, the generalhealth of the patient, the tolerance of the patient to various effectsof the administration, other drugs being administered to the patient,and like factors within the specific knowledge and expertise of thepatient or attending physician.

For daily administration, an appropriate dose can include, withoutlimitation, about 0.1 ng to about 100 mg, about 1 ng to about 10 mg perday or in another embodiment about 10 ng to about 1 mg per day.

Non-limiting examples of some components with their appropriateconcentration ranges and function are provided in Table 1 below.Particular examples of non-limiting formulations or compositions areprovided in Table 2.

TABLE 1 Example Components with Function and Concentration RangesIngredient Function Composition (% w/w) bimatoprost Active 0.03-1.0 carbomer Thickener 0.05-1.0  base Neutralizing Agent 0.01-2.0  ethanolPenetration enhancers 10-90 glycerin 1.0-20  diethylene glycol 1.0-50 monoethyl ether propylene glycol  1-50 polysorbate 20 0.1-5.0polysorbate 40 0.1-5.0 polysorbate 60 0.1-5.0 polysorbate 80 0.1-5.0PPG-5 ceteth-20 0.1-5.0 oleic acid 0.1-5.0 isostearyl isostearate0.1-10  isopropyl myristate 0.1-10  dipropylene glycol  1-50 dimethylether diethylene glycol  1-50 dipropylene glycol  1-50 caprylic/capric0.1-10  triglycerides benzyl alcohol Preservative 0.1-2.0 siliconeOcclusive Agent 0.1-10  water Vehicle  0-90

TABLE 2 Example Compositions Ingredient Function Composition (% w/w)bimatoprost Active 0.1 0.1 0.1 0.1 0.1 0.1 0.1 carbomer Thickener 0.100.15 0.125 0.10 0.20 0.25 0.25 NaOH (s) Neutralizing 0.035 Agent TEANeutralizing 0.22 0.18 0.15 0.22 0.38 0.38 Agent ethanol Penetration15.0 15.0 30.0 30.0 60.0 60.0 50.0 glycerin enhancers 5.0 diethyleneglycol 10.0 10.0 20.0 10 monoethyl ether propylene glycol 20 polysorbate20 4.0 4.0 4.0 water Vehicle 74.8 70.5 49.595 49.7 34.48 35.27 35.27

Example I Preparations of Bimatoprost Scalp Hair Growth Gel Compositions

Ethyl alcohol is weighed into a suitable media jar equipped for mixing,bimatoprost is then added to the ethyl alcohol and stirred at moderatespeed until bimatoprost is dissolved. Into separate mixing tank waterfor injection, glycerin, diethylene glycol monoethyl ether, andpropylene glycol are added and mixed until the solvents are dispersed.Ethyl alcohol/bimatoprost solution is then added into the water mixtureand mixed until the components are homogenously mixed (about 5 minutesof mixing). To the above mixture the carbomer thickener is added andmixed until well dispersed, once dispersed a base is added to thickenthe solution into a gel. Representative formulations made according tothe method above are shown in Table 3 below.

TABLE 3 Bimatoprost Scalp Hair Growth Topical Gel Formulations Bimat-Bimat- Bimat- Bimat- oprost oprost oprost oprost 0.03% 0.1% 0.3% 0.2%(Propylene (Propylene (Propylene (Propylene Ingredient Glycol) Glycol)Glycol) Glycol) (% w/w) Function Solution Solution Solution SolutionBimatoprost Active 0.03 0.1 0.3 0.2 Propylene Penetra- 10.0 10.0 10.010.0 glycol tion Diethylene enhancer 10.0 10.0 10.0 10.0 glycol mono-ethyl ether Ethyl alcohol 30.0 30.0 30.0 30.0 Glycerin 2.0 2.0 2.0 2.0Carbomer Thickener 0.15 0.15 0.15 0.15 (Ultrez 10) Triethanol- Neutral-0.16 0.16 0.16 0.16 amine izing agent Purified Vehicle 47.66 47.59 47.3947.49 water

Example II. In Vivo Treatment

A study is initiated to systematically evaluate the appearance of hairon the scalp and eyebrows who are administered bimatoprost gelformulations as in Table 3. The study involves 10 subjects, 5 male, 5female, average age 70 years, (ranging from 50-94 years). Each subjectis treated daily by the topical application of bimatoprost by the 0.3%w/w bimatoprost formulation of Table 3.

The study is limited to subjects who have administered bimatoprost formore than 3 months. The mean duration of exposure to the 0.3% w/wbimatoprost gel formulation prior to assessing the parameter of hair oreyebrow growth between the control and study eye is 129 days (range90-254 days). Observations are made under high magnification at a slitlamp biomicroscope. Documentation of differences between the control andtreatment areas is accomplished using a camera specially adapted for usewith a slit lamp biomicroscope.

The Results of the Observations Will be as Follows:

Length of hair and eyebrows: Increased length of hair in both groups isregularly observed. The difference in length varies from approximately10% to as much as 30%.

Number of hairs and eyebrows: Increased numbers of hairs are observed onthe scalp and eyebrows of each patient. The difference in number of hairand eyebrows varies from approximately 5% to as much as 30%. Whetherstatistically significant or not, bimatoprost with a penetrationenhancer will provide better and/or faster results than bimatoprostwithout a penetration enhancer.

The foregoing observations will establish that 0.03% w/w bimatoprostcomposition penetrates skin and grows hair.

Example III. Topical Cream

A topical 0.2% w/w bimatoprost cream is prepared as follows: Tegacid andspermaceti are melted together at a temperature of 70-80° C.Methylparaben is dissolved in about 500 gm of water and propyleneglycol, polysorbate 80, bimatoprost and a penetration enhancer are addedin turn, maintaining a temperature of 75-80° C. The methylparabenmixture is added slowly to the Tegacid and spermaceti melt, withconstant stirring. The addition is continued for at least 30 minuteswith additional stirring until the temperature has dropped to 40-45° C.Finally, sufficient water is added to bring the final weight to 1000 gmand the preparation stirred to maintain homogeneity until cooled andcongealed.

Example IV. Topical Cream

A 0.1% w/w bimatoprost topical cream is prepared as follows: Tegacid andspermaceti are melted together at a temperature of 70-80° C.Methylparaben is dissolved in water and propylene glycol, polysorbate80, bimatoprost and a penetration enhancer are added in turn,maintaining a temperature of 75-80° C. The methylparaben mixture isadded slowly to the Tegacid and spermaceti melt, with constant stirring.The addition is continued for at least 30 minutes with additionalstirring until the temperature has dropped to 40-45° C. Finally,sufficient water is added to bring the final weight to 1000 gm and thepreparation stirred to maintain homogeneity until cooled and congealed.

Example V. Topical Ointment

An Ointment Containing 2.0% w/w Bimatoprost is Prepared as Follows:

White petrolatum and wool fat are melted, strained and liquid petrolatumis added thereto. Bimatoprost, a penetration enhancer, zinc oxide, andcalamine are added to the remaining liquid petrolatum and the mixturemilled until the powders are finely divided and uniformly dispersed. Themixture is stirred into the white petrolatum, melted and cooled withstirring until the ointment congeals. In other variants, the zinc oxideand/or calamine can be omitted such that the formulation issubstantially free of the zinc oxide or calamine.

Example VI. Ointment

An ointment containing 5% w/w bimatoprost and a penetration enhancer isprepared by adding the active compound to light liquid petrolatum. Whitepetrolatum is melted together with wool fat, strained, and thetemperature adjusted to 45-50° C. The liquid petrolatum slurry is addedand the ointment stirred until congealed. The ointment can be packagedin 30 gm tubes.

Example VII. Spray Formulation

An aqueous spray formulation containing 0.03%, w/w bimatoprost and apenetration enhancer are prepared as follows. Bimatoprost and apenetration enhancer are dissolved in water and the resulting solutionis sterilized by filtration. The solution is aseptically filled intosterile containers with a spray nozzle for application on top of thehead. The formulation is as follows:

TABLE 4 Bimatoprost Spray Formulation of Example VII Ingredient (% w/w)Function Spray formulation Bimatoprost Active 0.03 Propylene glycolPenetration enhancer 5 Diethylene glycol 5 monoethyl ether Ethyl alcohol15 Light mineral oil — Ceteareth 12 — Glycerin 1 Carbomer (Ultrez 10)Thickener — Triethanolamine Neutralizing agent — Purified water Vehicle24 Hydrofluoro carbon, Propellant 49.97 hydrocarbon propellant, CO₂, or,Nitrogen

Example VIII. Lotion

A sample of bimatoprost and a penetration enhancer is dissolved in thevehicle of N-methyl pyrrolidone and propylene glycol to make a 0.5% w/wbimatoprost lotion for application to the scalp or other parts of thebody for growing hair.

Example IX. Aerosol

An aerosol containing approximately 0.1% w/w bimatoprost and apenetration enhancer is prepared by dissolving the bimatoprost and apenetration enhancer in absolute alcohol. The resulting solution isfiltered to remove particles and lint. This solution is chilled to about−30° C. A chilled mixture of dichlorodifluoromethane anddichlorotetrafluoroethane is then added to the solution. Thirteen mlplastic-coated amber bottles can be cold filled with 11.5 gm each of theresulting solution and capped. The aerosol may be sprayed onto the scalpor other parts of the body to grow hair.

Example X. Topical Foam Formulation

A 0.1% w/w bimatoprost topical foam formulation is prepared as follows:Methylparaben is dissolved in about 500 gm of water and propyleneglycol, polysorbate 80, bimatoprost and a penetration enhancer are addedin turn, maintaining a temperature of 75-80° C. The methylparabenmixture is added slowly to Tegacid and spermaceti, with constantstirring. The addition is continued for at least 30 minutes withadditional stirring until the temperature has dropped to 40-45° C.Finally, sufficient water is added to bring the final weight to 1000 gmand the preparation stirred to maintain homogeneity until cooled andcongealed.

An alternative foam formulation prepared in a similar manner as taughtin Example X in Table V is as follows:

Ingredient (% w/w) Function Foam formulation Bimatoprost Active 0.03Propylene glycol Penetration enhancer — Diethylene glycol 5 monoethylether Ethyl alcohol 10 Light mineral oil 6 Ceteareth 12 5 Glycerin —Carbomer (Ultrez 10) Thickener —

Example XI. Dusting Powder

A powder of the compound bimatoprost and a penetration enhancer isprepared by mixing in dry form with talcum powder at a weight/weightratio of 1:1:10.

Example XII. Related Compounds

Following the procedures of the preceding Examples, compositions aresimilarly prepared substituting an equimolar amount of a compound ofTable 1 for the bimatoprost disclosed in the preceding Examples.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,etc. used in the specification and claims are to be understood as beingmodified in all instances by the term “about.” “About” refers tovariations in concentrations of excipients and types of excipients whichare considered to be bioequivalent according to the FDA and otherregulatory authorities.

Example XIII

A 44 year old Caucasian male undergoing hair loss due to alopecia areataapplies once daily before sleeping the 0.1% w/w bimatoprost compositionof Table 3 for a period of 6 months. After 3 months of application, thesubject will notice new hair growth where there previously had been noneand darkening of the follicles of old hair. Observations of new hairgrowth are made under high magnification at the slit lamp biomicroscopeand by computer assisted image analysis. Documentation of differencesbetween the control and treatment areas is accomplished using a cameraspecially adapted for use with the slit lamp biomicroscope.

Example XIV

A 37 year old Hispanic male suffering from male pattern baldness due toandrogenetic alopecia applies the 0.2% w/w bimatoprost composition ofTable 3 twice daily in areas where hair is noticeably thinning. After 63days of application, increased growth of hair will be noticed as will benew hair growth as measured by high magnification at the slit lampbiomicroscope and by computer assisted image analysis. Aftersatisfactory levels of hair growth are observed, the patient applies the0.2% w/w bimatoprost composition only twice a week.

Example XV

A 29 year old Caucasian healthy female wishes to have fuller hair andmore hair growth even though no disease or hair loss condition has beendiagnosed by doctors. The patient will apply the 0.3% w/w bimatoprostcomposition of Table 3 once daily until more hair growth is observedafter approximately three months of use. The patient continues to applythe composition once a week to maintain the increased hair growth.

Example XVI

A 35 year old African American male diagnosed with folliculardegeneration syndrome and associated hair loss will apply the 0.03% w/wbimatoprost composition of Table 3. The composition will be appliedtwice daily, once in the morning after showering and once in theevening. After 46 days of application, increased hair growth will benoticed and easing of the symptoms of follicular degeneration syndrome.The patient continues application for another 6 months.

What is claimed is:
 1. A composition for growing hair by topicalapplication comprising: at least one penetration enhancer; and 0.01% to0.3% w/w cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compoundrepresented by the formula I:

wherein the dashed bonds represent the presence or absence of a doublebond which can be in the cis or trans configuration, A is an alkylene oralkenylene radical having from two to six carbon atoms, which radicalcan be interrupted by one or more oxa radicals and substituted with oneor more hydroxy, oxo, alkyloxy or akylcarboxy groups wherein the alkylradical comprises from one to six carbon atoms; B is a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from the group consisting of hydrogen, a lower alkyl radicalhaving from four to ten carbon atoms wherein the heteroatom is selectedfrom the group consisting of nitrogen, oxygen and sulfur atoms; X is—N(R₄)₂ wherein R₄ is selected from the group consisting of hydrogen, alower alkyl radical having from one to six carbon atoms,

wherein R₅ is a lower alkyl radical having from one to six carbon atoms;Z is ═O; one of R₁ and R₂ is ═O, —OH or a —O(CO)R₆ group, and the otherone is —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or —(CH₂)mR₇ wherein m is 0 or an integer of from1 to 10, and R₇ is cycloalkyl radical, having from three to seven carbonatoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above infree form or a pharmaceutically acceptable salt thereof, in associationwith a penetration enhancer in particular formulations adapted fortopical application to mammalian skin; wherein said composition isformulated for topical administration to the skin.
 2. The compositionaccording to claim 1 wherein said cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl compound represented by the formula I isbimatoprost.
 3. The composition according to claim 1 wherein thepenetrating enhancer is selected from the group consisting of propyleneglycol, diethylene glycol monoether, ethyl alcohol and glycerin.
 4. Thecomposition according to claim 1 wherein the penetrating enhancer isselected from the group consisting of at least two compounds selectedfrom the group consisting of propylene glycol, diethylene glycolmonoether, ethyl alcohol and glycerin.
 5. A composition according toclaim 1 wherein the penetrating enhancer consists of the followingcompounds: propylene glycol, diethylene glycol monoether, ethyl alcoholand glycerin.
 6. A composition according to claim 1 comprising from0.03-0.3% w/w bimatoprost, about 10% w/w propylene glycol, about 10% w/wdiethylene glycol monoether, about 30% w/w ethyl alcohol, about 2% w/wglycerin, about 0.15% w/w carbomer, about 0.16% w/w triethanolamine, andpurified water.
 7. The composition according to claim 6 comprising 0.03%w/w bimatoprost.
 8. The composition of claim 6 wherein the compositioncomprises 0.1% w/w bimatoprost.
 9. The composition of claim 6 whereinthe composition comprises 0.2% bimatoprost.
 10. The composition of claim6 wherein the composition consists of 0.3% w/w bimatoprost.
 11. Thecomposition according to claim 6 wherein the composition is in the formof one selected from the group consisting of solutions, gels, ointments,foams, films, liniments, creams, shampoos, lotions, pastes, jellies,sprays and aerosols.
 12. The composition of claim 11 wherein thecomposition is packaged in a kit with an applicator for application tothe skin.
 13. A method for stimulating hair growth comprising topicallyadministering a composition comprising: at least one penetrationenhancer; and a cyclopentane heptanoic acid, 2-cycloalkyl or arylalkylcompound represented by the formula I:

wherein the dashed bonds represent the presence or absence of a doublebond which can be in the cis or trans configuration, A is an alkylene oralkenylene radical having from two to six carbon atoms, which radicalcan be interrupted by one or more oxa radicals and substituted with oneor more hydroxy, oxo, alkyloxy or akylcarboxy groups wherein the alkylradical comprises from one to six carbon atoms; B is a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from the group consisting of hydrogen, a lower alkyl radicalhaving from four to ten carbon atoms wherein the heteroatom is selectedfrom the group consisting of nitrogen, oxygen and sulfur atoms; X is—N(R₄)₂ wherein R₄ is selected from the group consisting of hydrogen, alower alkyl radical having from one to six carbon atoms,

wherein R₅ is a lower alkyl radical having from one to six carbon atoms;Z is ═O; one of R₁ and R₂ is ═O, —OH or a —O(CO)R₆ group, and the otherone is —OH or —O(CO) R₆, or R₁ is ═O and R₂ is H, wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or —(CH₂)mR₇ wherein m is 0 or an integer of from1 to 10, and R₇ is cycloalkyl radical, having from three to seven carbonatoms, or a hydrocarbyl aryl or heteroaryl radical, as defined above infree form or a pharmaceutically acceptable salt thereof, in associationwith a penetration enhancer in particular formulations adapted fortopical application to mammalian skin; wherein said composition isformulated for topical administration to the skin.
 14. The methodaccording to claim 13 wherein said cyclopentane heptanoic acid,2-cycloalkyl or arylalkyl compound represented by the formula I isbimatoprost.
 15. The method according to claim 14 comprising bimatoprostat a concentration of about 0.03% w/w to about 0.3% w/w.
 16. The methodaccording to claim 14 comprising bimatoprost at about 0.1% w/w; about10% w/w propylene glycol, about 10% w/w diethylene glycol monoether,about 30% w/w ethyl alcohol, about 2% w/w glycerin, about 0.15% w/wcarbomer, about 0.16% w/w triethanolamine, and purified water.
 17. Themethod according to according to claim 14 comprising bimatoprost atabout 0.3% w/w; about 10% w/w propylene glycol, about 10% w/w diethyleneglycol monoether, about 30% w/w ethyl alcohol, about 2% w/w glycerin,about 0.15% w/w carbomer, about 0.16% w/w triethanolamine, and purifiedwater.
 18. The method according to claim 14, wherein the composition isapplied at least once daily to the scalp.
 19. The method according toclaim 14, wherein the composition is applied at least once daily to thescalp for treatment of one of the following conditions selected from thegroup consisting of alopecia areata, telogen effluvium, anageneffluvium, cicatricial alopecia, scarring alopecia; hair shaftabnormalities, trichorrexis nodosa, loose anagen syndrome,trichotillomania, traction alopecia; infectious hair disorders, tinieacapitis, sebohorreic dermatitis, follicullitus of the scalp, andandrogenetic alopecia.
 20. The method according to claim 14 wherein thecomposition is applied at least once a day to both the scalp and theeyebrows for patients experiencing hair loss due to chemotherapy,hormonal imbalance, fungal infection of the scalp, anti-coagulants,medicine for gout, depression, high blood pressure and heart disease.